Cellular copper homeostasis: current concepts on its interplay with glutathione homeostasis and its implication in physiology and human diseases

Metallomics ◽  
2017 ◽  
Vol 9 (10) ◽  
pp. 1376-1388 ◽  
Author(s):  
Ashima Bhattacharjee ◽  
Kaustav Chakraborty ◽  
Aditya Shukla
Keyword(s):  
Trace Element ◽  
Copper Homeostasis ◽  
Human Diseases ◽  
Living Organisms ◽  
Cellular Copper ◽  
Almost All ◽  
Glutathione Homeostasis ◽  
Intracellular Copper

Copper is a trace element essential for almost all living organisms, however the level of intracellular copper needs to be tightly regulated. This review explores the existing literature on the role of glutathione in regulating cellular copper homeostasis.

scholarly journals Involvement of Various Enzymes in the Physiology and Pathogenesis of Streptococcus suis

2020 ◽  
Vol 7 (4) ◽  
pp. 143
Author(s):  
Chengkun Zheng ◽  
Man Wei ◽  
Mengdie Jia ◽  
ManMan Cao
Keyword(s):  
Streptococcus Suis ◽  
Infection Process ◽  
Swine Industry ◽  
Serine Threonine Kinase ◽  
Future Directions ◽  
Threonine Kinase ◽  
Severe Infections ◽  
Living Organisms ◽  
Almost All

Streptococcus suis causes severe infections in both swine and humans, making it a serious threat to the swine industry and public health. Insight into the physiology and pathogenesis of S. suis undoubtedly contributes to the control of its infection. During the infection process, a wide variety of virulence factors enable S. suis to colonize, invade, and spread in the host, thus causing localized infections and/or systemic diseases. Enzymes catalyze almost all aspects of metabolism in living organisms. Numerous enzymes have been characterized in extensive detail in S. suis, and have shown to be involved in the pathogenesis and/or physiology of this pathogen. In this review, we describe the progress in the study of some representative enzymes in S. suis, such as ATPases, immunoglobulin-degrading enzymes, and eukaryote-like serine/threonine kinase and phosphatase, and we highlight the important role of various enzymes in the physiology and pathogenesis of this pathogen. The controversies about the current understanding of certain enzymes are also discussed here. Additionally, we provide suggestions about future directions in the study of enzymes in S. suis.

The role of endoplasmic reticulum stress in lead (Pb)-induced mitophagy of HEK293 cells

2020 ◽  
Vol 36 (12) ◽  
pp. 1002-1009
Author(s):  
Ke Gao ◽  
Chengfei Zhang ◽  
Yihong Tian ◽  
Sajid Naeem ◽  
Yingmei Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Damage ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Pb Toxicity ◽  
Hsp60 Expression ◽  
Living Organisms ◽  
Almost All

It is well-documented that lead (Pb) toxicity can affect almost all systems in living organisms. It can induce selective autophagy of mitochondria (mitophagy) by triggering reactive oxygen species production. Emerging evidence has suggested that Pb-induced autophagy can also be activated by the endoplasmic reticulum (ER) stress pathway. However, the interplay between ER stress and mitophagy remains to be elucidated. In this study, human embryonic kidney HEK293 cells were employed to investigate the role of ER stress in Pb-induced mitophagy. The results showed that the cell viability was decreased and cell damage was induced after exposure to Pb (0, 0.5, 1, 2, and 4 mM) for 24 h in a dose-dependent manner. Moreover, the expression of LC3-Ⅱ was significantly increased, and the expression of HSP60 was dramatically decreased after exposure to 1 mM and 2 mM Pb, indicating the induction of mitophagy following Pb exposure. Meanwhile, the expressions of activating transcription factor 6, inositol-requiring protein-1α, CCAAT/enhancer binding protein homologous protein, and glucose-regulated protein 78 were dramatically increased after Pb treatment, signifying the initiation of ER stress. Notably, the mitophagic effect was significantly compromised when ER stress was inhibited by 0.5 mM 4-phenylbutyrate, which was evidenced by lesser decreases in HSP60 expression and level of LC3-Ⅱ, suggesting Pb-induced mitophagy may be activated by the ER stress. Taken together, these findings provide a better understanding of Pb toxicity and suggest that Pb-induced ER stress may play a regulatory role in the upstream of mitophagy.

scholarly journals Ratiometric two-photon microscopy reveals attomolar copper buffering in normal and Menkes mutant cells

2019 ◽  
Vol 116 (25) ◽  
pp. 12167-12172 ◽  
Author(s):  
M. Thomas Morgan ◽  
Daisy Bourassa ◽  
Shefali Harankhedkar ◽  
Adam M. McCallum ◽  
Stephanie A. Zlatic ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Storage Proteins ◽  
Copper Homeostasis ◽  
Binding Affinities ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Photon Excitation ◽  
Rapid Kinetics ◽  
Cellular Copper ◽  
Intracellular Copper

Copper is controlled by a sophisticated network of transport and storage proteins within mammalian cells, yet its uptake and efflux occur with rapid kinetics. Present as Cu(I) within the reducing intracellular environment, the nature of this labile copper pool remains elusive. While glutathione is involved in copper homeostasis and has been assumed to buffer intracellular copper, we demonstrate with a ratiometric fluorescent indicator, crisp-17, that cytosolic Cu(I) levels are buffered to the vicinity of 1 aM, where negligible complexation by glutathione is expected. Enabled by our phosphine sulfide-stabilized phosphine (PSP) ligand design strategy, crisp-17 offers a Cu(I) dissociation constant of 8 aM, thus exceeding the binding affinities of previous synthetic Cu(I) probes by four to six orders of magnitude. Two-photon excitation microscopy with crisp-17 revealed rapid, reversible increases in intracellular Cu(I) availability upon addition of the ionophoric complex CuGTSM or the thiol-selective oxidant 2,2′-dithiodipyridine (DTDP). While the latter effect was dramatically enhanced in 3T3 cells grown in the presence of supplemental copper and in cultured Menkes mutant fibroblasts exhibiting impaired copper efflux, basal Cu(I) availability in these cells showed little difference from controls, despite large increases in total copper content. Intracellular copper is thus tightly buffered by endogenous thiol ligands with significantly higher affinity than glutathione. The dual utility of crisp-17 to detect normal intracellular buffered Cu(I) levels as well as to probe the depth of the labile copper pool in conjunction with DTDP provides a promising strategy to characterize perturbations of cellular copper homeostasis.

scholarly journals PLEKHA5, PLEKHA6 and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis

2021 ◽  
Author(s):  
Sandra Citi ◽  
Sophie Sluysmans ◽  
Isabelle Mean ◽  
Tong Xiao ◽  
Amina Boukhatemi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Copper Homeostasis ◽  
Cell Periphery ◽  
Ww Domains ◽  
C Terminus ◽  
Menkes Atpase ◽  
Junctional Protein ◽  
Cellular Copper ◽  
And Function

Copper homeostasis is crucial for cellular physiology and development, and its dysregulation leads to disease. The Menkes ATPase ATP7A plays a key role in copper efflux, by trafficking from the Golgi to the plasma membrane upon cell exposure to elevated copper, but the mechanisms that target ATP7A to the cell periphery are poorly understood. PDZD11 interacts with the C-terminus of ATP7A, which contains sequences involved in ATP7A trafficking, but the role of PDZD11 in ATP7A localization is unknown. Here we identify PLEKHA5 and PLEKHA6 as new interactors of PDZD11, which similarly to the junctional protein PLEKHA7 bind to PDZD11 N-terminus through their WW domains. Using CRISPR-KO kidney epithelial cells, we show by immunofluorescence that WW-PLEKHAs (PLEKHA5, PLEKHA6, PLEKHA7) recruit PDZD11 to distinct plasma membrane localizations, and that they are required for the efficient anterograde targeting of ATP7A to the cell periphery in elevated copper. Pulldown experiments show that WW-PLEKHAs promote PDZD11 interaction with the C-terminus of ATP7A. However, WW-PLEKHAs and PDZD11 are not necessary for ATP7A Golgi localization in basal copper, ATP7A copper-induced exit from the Golgi, and ATP7A retrograde trafficking to the Golgi. Finally, measuring bioavailable copper with the labile copper probe CF4 shows that WW-PLEKHAs and PDZD11 are required to maintain low intracellular copper levels when cells are exposed to elevated copper. These data indicate that WW-PLEKHAs-PDZD11 complexes regulate the localization and function of ATP7A to modulate cellular copper homeostasis.

scholarly journals Alkaline Phosphatase in Stem Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Kateřina Štefková ◽  
Jiřina Procházková ◽  
Jiří Pacherník
Keyword(s):  
Stem Cells ◽  
Alkaline Phosphatase ◽  
Embryonic Stem ◽  
Stem Cell Marker ◽  
Developmental Studies ◽  
Alkaline Phosphatases ◽  
Potential Significance ◽  
Living Organisms ◽  
Almost All

Alkaline phosphatase is an enzyme commonly expressed in almost all living organisms. In humans and other mammals, determinations of the expression and activity of alkaline phosphatase have frequently been used for cell determination in developmental studies and/or within clinical trials. Alkaline phosphatase also seems to be one of the key markers in the identification of pluripotent embryonic stem as well as related cells. However, alkaline phosphatases exist in some isoenzymes and isoforms, which have tissue specific expressions and functions. Here, the role of alkaline phosphatase as a stem cell marker is discussed in detail. First, we briefly summarize contemporary knowledge of mammalian alkaline phosphatases in general. Second, we focus on the known facts of its role in and potential significance for the identification of stem cells.

scholarly journals COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A

2015 ◽  
Vol 26 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Christine A. Phillips-Krawczak ◽  
Amika Singla ◽  
Petro Starokadomskyy ◽  
Zhihui Deng ◽  
Douglas G. Osborne ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Mechanistic Explanation ◽  
Copper Accumulation ◽  
Endosomal Trafficking ◽  
Copper Transporter ◽  
Early Endosomes ◽  
Evolutionarily Conserved ◽  
Carboxyl Terminal ◽  
Intracellular Copper

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.

Neuron-glia: understanding cellular copper homeostasis, its cross-talk and their contribution towards neurodegenerative diseases

Metallomics ◽  
2020 ◽  
Author(s):  
Ashima Bhattacharjee ◽  
Sandeepan Ghosh ◽  
Ajanta Chatterji ◽  
Kaustav Chakraborty
Keyword(s):  
Neurodegenerative Diseases ◽  
Cross Talk ◽  
Copper Homeostasis ◽  
Cell Types ◽  
Principal Cell ◽  
Cellular Copper

The review focuses on the role of the copper homeostasis in the principal cell types of the CNS and its role in neurodegenration.

Structure and function of 5S rRNA in the ribosome

1995 ◽  
Vol 73 (11-12) ◽  
pp. 869-876 ◽  
Author(s):  
Alexey A. Bogdanov ◽  
Olga A. Dontsova ◽  
Svetlana S. Dokudovskaya ◽  
Inna N. Lavrik
Keyword(s):  
Ribosomal Proteins ◽  
5S Rrna ◽  
23S Rrna ◽  
Order Structure ◽  
Structural Domain ◽  
Experimental Approaches ◽  
Living Organisms ◽  
Almost All ◽  
And Function

5S rRNA is a small RNA molecule that is a component of a ribosome from almost all living organisms. In this review, we discuss the biogenesis of 5S rRNA and its properties as an independent structural domain of a ribosome as well as the current concepts concerning the higher order structure of 5S rRNA in free state and in its complexes with ribosomal proteins and its folding in the ribosome. Special attention is paid to recent experimental approaches that have been useful in 5S rRNA studies. Our own data on topography of 5S rRNA in the ribosomes are discussed in detail. The hypothesis describing the possible functional role of 5S rRNA for ribosome functioning is discussed.Key words: 5S rRNA, ribosomes, 23S rRNA, site-directed chemical cross-linking, RNA folding.

scholarly journals PLEKHA5, PLEKHA6 and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis

2021 ◽  
Author(s):  
Sophie Sluysmans ◽  
Isabelle Méan ◽  
Tong Xiao ◽  
Amina Boukhatemi ◽  
Flavio Ferreira ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Copper Homeostasis ◽  
Cell Periphery ◽  
Ww Domains ◽  
C Terminus ◽  
Menkes Atpase ◽  
Junctional Protein ◽  
Cellular Copper ◽  
And Function

Copper homeostasis is crucial for cellular physiology and development, and its dysregulation leads to disease. The Menkes ATPase ATP7A plays a key role in copper efflux, by trafficking from the Golgi to the plasma membrane upon cell exposure to elevated copper, but the mechanisms that target ATP7A to the cell periphery are poorly understood. PDZD11 interacts with the C-terminus of ATP7A, which contains sequences involved in ATP7A trafficking, but the role of PDZD11 in ATP7A localization is unknown. Here we identify PLEKHA5 and PLEKHA6 as new interactors of PDZD11, which bind to PDZD11 N-terminus through their WW domains similarly to the junctional protein PLEKHA7. Using CRISPR-KO kidney epithelial cells, we show by immunofluorescence microscopy that WW-PLEKHAs (PLEKHA5, PLEKHA6, PLEKHA7) recruit PDZD11 to distinct plasma membrane localizations, and that they are required for the efficient anterograde targeting of ATP7A to the cell periphery in elevated copper conditions. Pulldown experiments show that WW-PLEKHAs promote PDZD11 interaction with the C-terminus of ATP7A. However, WW-PLEKHAs and PDZD11 are not necessary for ATP7A Golgi localization in basal copper, ATP7A copper-induced exit from the Golgi, and ATP7A retrograde trafficking to the Golgi. Finally, measuring bioavailable and total cellular copper, metallothionein-1 expression and cell viability shows that WW-PLEKHAs and PDZD11 are required to maintain low intracellular copper levels when cells are exposed to elevated copper. These data indicate that WW-PLEKHAs-PDZD11 complexes regulate the localization and function of ATP7A to promote copper extrusion in elevated copper.

scholarly journals Copper dependent ERK1/2 phosphorylation is essential for the viability of neurons and not glia

2021 ◽  
Author(s):  
Kaustav Chakraborty ◽  
Sumanta Kar ◽  
Bhawana Rai ◽  
Reshma Bhagat ◽  
Nabanita Naskar ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Ion Homeostasis ◽  
Fetal Brain ◽  
Systematic Investigation ◽  
Glial Differentiation ◽  
Copper Transporter ◽  
Neuronal Progenitor ◽  
Cellular Copper ◽  
Intracellular Copper

AbstractIntracellular Copper [Cu(I)] has been hypothesized to play role in the differentiation of the neurons. This necessitates understanding the role of Cu(I) not only in the neurons but also in the glia considering their anatomical proximity, contribution towards ion homeostasis, neuronal physiology, and neurodegeneration. In this study we did a systematic investigation of the changes in the cellular copper homeostasis during neuronal and glial differentiation and the pathways triggered by them. Our study demonstrates increased mRNA for the plasma membrane copper transporter CTR1 leading to an increased Cu(I) during neuronal (PC-12) differentiation. ATP7A is retained in the Trans Golgi Network (TGN) despite high Cu(I) demonstrating its utilization in triggering the pathways towards the neuronal differentiation. One of these pathways is ERK1/2 phosphorylation accompanying the differentiation of both PC-12 and human fetal brain derived neuronal progenitor cells. The study demonstrates that the ERK1/2 phosphorylation is essential for the viability of the neurons. In contrast, differentiated C-6 (glia) cells contain low intracellular copper and significant downregulation of the ERK1/2 phosphorylation. Interestingly ATP7A shows vesicular localization despite the low copper in the glia. In addition to the TGN in the perinuclear region, ATP7A localizes into RAB11 positive recycling endosomes in the glial neurites, not observed in the neurons. Our study demonstrates role of the copper dependent ERK1/2 phosphorylation in the neuronal differentiation. Whereas glial differentiation largely involves sequestration of Cu(I) into the endosomes potentially (i) for ready release to the neurons (ii) rendering cytosolic copper unavailable for pathways like the ERK1/2 activation.

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